We propose to test for genetic heterogeneity within juvenile insulin dependent diabetes (JIDD) by studying approximately 100 Caucasian famillies with two or more affected sibling (multiplex kindreds). We propose specifically to delineate homogeneous subgroups by the use of the following biochemical and immunologic markers, in addition to predigree and clinical information: HLA typing for loci A, B, C and D, chromosome 6 polymorphisms (properdin factor b and gloxylase I), islet cell antibodies, thyrogastric antibodies, and(in treated diabetics) insulin antibodies, glycosylated hgb Alc and C-peptide. Using these markers, we will test subgroups for intra-familial constancy within groups and interfamily variation between groups. Linkage analysis between HLA haplotypes and other chromosome 6 polymorphisms will be performed for each subgroup. Mathematical models will be developed as well as methods of analysis that will handle the complexities of heterogeneity. These will be applied for the purpose of defining the underlying genetic mechanisms for each subgroup insofar as possible. As subgroups are defined they will receive more intensive metabolic testing to develop the data with which to identify the at-risk individuals, so that more accurate genetic counseling can be offered to such families in the future.